CA2149273A1 - Process for the preparation of 2-amino-4,6-dichloro-pyrimidine - Google Patents
Process for the preparation of 2-amino-4,6-dichloro-pyrimidineInfo
- Publication number
- CA2149273A1 CA2149273A1 CA002149273A CA2149273A CA2149273A1 CA 2149273 A1 CA2149273 A1 CA 2149273A1 CA 002149273 A CA002149273 A CA 002149273A CA 2149273 A CA2149273 A CA 2149273A CA 2149273 A1 CA2149273 A1 CA 2149273A1
- Authority
- CA
- Canada
- Prior art keywords
- amino
- excess
- preparation
- dichloropyrimidine
- phosphorus oxychloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Process for the preparation of 2-amino-4,6-dichloropyrimidine by reaction of 2-amino-4,6-dihydroxy-pyrim;dine with an excess of phosphorus oxychloride at 20 to 80°C and in the presence of triethylamine as the acid-trapping agent.
Description
Process for the preparation of 2-amino-4,6-dichloro-pyrimidine 2-Amino-4,6-dichloropyr; m; dine (ADCP) is a known and valuable intermediate product for medicaments and agrochemicals.
A few processes for the preparation of ADCP are therefore already known from the literature. A process is thus described, for example, in US 3,991,190, Example 1, in which 2-amino-4,6-dihydroxypyrimidine (ADHP) is reacted with an excess of phosphorusoxychloride and dimethylAn;line, as an acid-trapping agent, while boiling under reflux at a tèmperature of about 107C to give ADCP. After excess phosphorusoxychloride has been dis-tilled off, ADCP is isolated in this process by suspen-sion in water and addition of sodium hydroxide solutionuntil a pH of 8 to 9 is reached. In this process, how-ever, a large number of by-products is formed and the yield of ADCP is relatively low (70%). As a proposal for improvement of the process, US 4,929,729 describes the reaction of ADHP with phosphorusoxychloride at tempera-tures of 50 - 100C in the presence of an acid-trapping agent in an additional solvent. The yield of ADCP is about 10% higher than in US 3,991,190 (82 - 85%), the purity being about 91 - 95%. The disadvantage of this process, however, is the need for an additional solvent.
Another disadvantage is that, as carried out in the examples of US 4,929,729, to isolate the ADCP the reac-tion mixture has to be poured onto ice-water, after the chlorination has been carried out and the excess phospho-rusoxychloride and the solvent have been separated off,and then has to be heated again to about 50C, for which an additional expenditure of energy is necessary.
The object of the present invention was accord-ingly to discover a process for the preparation of 2-A~ino-4,6-dichloropyrimidine which, without an additional solvent, leads to ADCP in a higher yield and higher purity than the prior art, prevents the formation of by-products and avoids the additional e~renAiture of energy .
during isolation of the ADCP.
Unexpectedly, it has been possible to achieve this object by the process according to the invention.
The present invention therefore relates to a process for the preparation of 2-~ino-4,6-dichloropyrim-idine, which is characterized in that 2-~ino-4,6-dihydr-oxypyrimidine is reacted with an excess of phosphorus oxychloride at a temperature of 20 to 80C in the presence of triethyl~;ne as the acid-trapping agent, and 2-P~ino-4,6-dichloropyrimidine is isolated.
In the process according to the invention, 2-amino-4,6-dihydroxypyrimidine (ADHP) is reacted with an excess of POCl3 to give 2-~m;no-4,6-dichloropyrimidine (ADCP).
For this, the ADHP is suspended in POCl3, which serves both as the reagent and as the reaction medium, which means that no additional solvent or diluent is necessary.
The ease of handling the suspension is determined by the amount of POC13 employed. The molar ratio of ADHP to POCl3 can be varied here, the lower li~;t being influenced by the stirrability of the suspension and the upper limit being influenced chiefly by economic factors.
A molar ratio of ADHP to POC13 of 1 : 3 to 1 : 8, partic-ularly preferably 1 : 4 to 1 : 6, is preferably employed.
A larger excess of POCl3 has no adverse effects on the reaction, and if desired can also be employed, but is not appropriate for economic reasons.
The suspension thus obt~ine~ is then heated to a tempera-ture of 20 - 80C. The more viscous the suspension to be heated, the higher the temperature should be in order to allow adequate stirrability and therefore thorough mixing. The suspension is preferably heated to 40 to 80C, particularly preferably to 70 to 75C.
Triethylamine is then metered into the mixture in an equivalent amount over a period of about 20 to 35 80 minutes, preferably 30 to 60 minutes. However, a slight excess of triethylamine can also be used, so that the molar ratio of ADHP to triethylamine is about 1 : 2 to 1 : 3, preferably 1 : 2.25.
When the metering has ended, stirring is 21~9273 _ continued at the reaction temperature for about a further 2 to 10 minutes, preferably 4 to 6 minutes. To isolate and work up the ADCP, the excess POC13 is distilled off in vacuo. The bottom temperature can vary here, according S to the vacuum achieved, the lower limit being influenced by the stirrability of the reaction mixture and the upper limit being about 80C. The bottom temperature is prefer-ably kept at about 70 to 75C. The residue is stirred into water at a temperature of about 40 to 60C. The suspension thus obtained is stirred at about 40 to 60C
for about a further 1.5 to 2.5 hours, and 20 to 50%
strength, preferably 20% strength, NaOH is then added until a pH of about 2.5 to 4, preferably about 3, is reached.
Finally, the product which has precipitated out is filtered off, washed with water and dried in air. ADCP
is obtained by the process according to the invention in yields of more than 90% and in a purity (about 99%) that are higher than in the prior art.
Example 1 100 ml (1.12 mol) of phosphorus oxychloride and 25.4 g (0.2 mol) of 2-amino-4,6-dihydroxypyrimidine were initially introduced in succession into a 250 ml double-walled glass reactor with a stirrer, reflux condenser and thermostat heating. The suspension thus obtained was heated to 75C, and 46 g (0.45 mol) of triethylamine were then metered in over a period of 1 hour. When the metering had ended, the mixture was stirred at 75C for a further 5 minutes and excess phosphorus oxychloride was then distilled off in vacuo, the bottom temperature being kept at about 75C. The residue was stirred into 200 ml of water at a temperature of about 50C and stirring of the suspension thus obtA;ne~ was continued at 50C for a further 2 hours. 20% strength NaOH was then added to the suspension until a pH of 3 was reached.
The product which had precipitated out was filtered off, washed with water and dried in air.
Yield: 30.2 g (92.1~) Content from GC: 99%
A few processes for the preparation of ADCP are therefore already known from the literature. A process is thus described, for example, in US 3,991,190, Example 1, in which 2-amino-4,6-dihydroxypyrimidine (ADHP) is reacted with an excess of phosphorusoxychloride and dimethylAn;line, as an acid-trapping agent, while boiling under reflux at a tèmperature of about 107C to give ADCP. After excess phosphorusoxychloride has been dis-tilled off, ADCP is isolated in this process by suspen-sion in water and addition of sodium hydroxide solutionuntil a pH of 8 to 9 is reached. In this process, how-ever, a large number of by-products is formed and the yield of ADCP is relatively low (70%). As a proposal for improvement of the process, US 4,929,729 describes the reaction of ADHP with phosphorusoxychloride at tempera-tures of 50 - 100C in the presence of an acid-trapping agent in an additional solvent. The yield of ADCP is about 10% higher than in US 3,991,190 (82 - 85%), the purity being about 91 - 95%. The disadvantage of this process, however, is the need for an additional solvent.
Another disadvantage is that, as carried out in the examples of US 4,929,729, to isolate the ADCP the reac-tion mixture has to be poured onto ice-water, after the chlorination has been carried out and the excess phospho-rusoxychloride and the solvent have been separated off,and then has to be heated again to about 50C, for which an additional expenditure of energy is necessary.
The object of the present invention was accord-ingly to discover a process for the preparation of 2-A~ino-4,6-dichloropyrimidine which, without an additional solvent, leads to ADCP in a higher yield and higher purity than the prior art, prevents the formation of by-products and avoids the additional e~renAiture of energy .
during isolation of the ADCP.
Unexpectedly, it has been possible to achieve this object by the process according to the invention.
The present invention therefore relates to a process for the preparation of 2-~ino-4,6-dichloropyrim-idine, which is characterized in that 2-~ino-4,6-dihydr-oxypyrimidine is reacted with an excess of phosphorus oxychloride at a temperature of 20 to 80C in the presence of triethyl~;ne as the acid-trapping agent, and 2-P~ino-4,6-dichloropyrimidine is isolated.
In the process according to the invention, 2-amino-4,6-dihydroxypyrimidine (ADHP) is reacted with an excess of POCl3 to give 2-~m;no-4,6-dichloropyrimidine (ADCP).
For this, the ADHP is suspended in POCl3, which serves both as the reagent and as the reaction medium, which means that no additional solvent or diluent is necessary.
The ease of handling the suspension is determined by the amount of POC13 employed. The molar ratio of ADHP to POCl3 can be varied here, the lower li~;t being influenced by the stirrability of the suspension and the upper limit being influenced chiefly by economic factors.
A molar ratio of ADHP to POC13 of 1 : 3 to 1 : 8, partic-ularly preferably 1 : 4 to 1 : 6, is preferably employed.
A larger excess of POCl3 has no adverse effects on the reaction, and if desired can also be employed, but is not appropriate for economic reasons.
The suspension thus obt~ine~ is then heated to a tempera-ture of 20 - 80C. The more viscous the suspension to be heated, the higher the temperature should be in order to allow adequate stirrability and therefore thorough mixing. The suspension is preferably heated to 40 to 80C, particularly preferably to 70 to 75C.
Triethylamine is then metered into the mixture in an equivalent amount over a period of about 20 to 35 80 minutes, preferably 30 to 60 minutes. However, a slight excess of triethylamine can also be used, so that the molar ratio of ADHP to triethylamine is about 1 : 2 to 1 : 3, preferably 1 : 2.25.
When the metering has ended, stirring is 21~9273 _ continued at the reaction temperature for about a further 2 to 10 minutes, preferably 4 to 6 minutes. To isolate and work up the ADCP, the excess POC13 is distilled off in vacuo. The bottom temperature can vary here, according S to the vacuum achieved, the lower limit being influenced by the stirrability of the reaction mixture and the upper limit being about 80C. The bottom temperature is prefer-ably kept at about 70 to 75C. The residue is stirred into water at a temperature of about 40 to 60C. The suspension thus obtained is stirred at about 40 to 60C
for about a further 1.5 to 2.5 hours, and 20 to 50%
strength, preferably 20% strength, NaOH is then added until a pH of about 2.5 to 4, preferably about 3, is reached.
Finally, the product which has precipitated out is filtered off, washed with water and dried in air. ADCP
is obtained by the process according to the invention in yields of more than 90% and in a purity (about 99%) that are higher than in the prior art.
Example 1 100 ml (1.12 mol) of phosphorus oxychloride and 25.4 g (0.2 mol) of 2-amino-4,6-dihydroxypyrimidine were initially introduced in succession into a 250 ml double-walled glass reactor with a stirrer, reflux condenser and thermostat heating. The suspension thus obtained was heated to 75C, and 46 g (0.45 mol) of triethylamine were then metered in over a period of 1 hour. When the metering had ended, the mixture was stirred at 75C for a further 5 minutes and excess phosphorus oxychloride was then distilled off in vacuo, the bottom temperature being kept at about 75C. The residue was stirred into 200 ml of water at a temperature of about 50C and stirring of the suspension thus obtA;ne~ was continued at 50C for a further 2 hours. 20% strength NaOH was then added to the suspension until a pH of 3 was reached.
The product which had precipitated out was filtered off, washed with water and dried in air.
Yield: 30.2 g (92.1~) Content from GC: 99%
Claims (4)
1. Process for the preparation of 2-amino-4,6-dichlo-ropyrimidine, characterized in that 2-amino-4,6-dihydro-xypyrimidine is reacted with an excess of phosphorus oxychloride at a temperature of 20 to 80°C in the presence of triethylamine as the acid-trapping agent, and
2-amino-4,6-dichloropyrimidine is isolated.
2. Process according to claim 1, characterized in that the 2-amino-4,6-dihydroxypyrimidine and phosphorus oxychloride are employed in a molar ratio of 1 : 3 to 1 : 8.
2. Process according to claim 1, characterized in that the 2-amino-4,6-dihydroxypyrimidine and phosphorus oxychloride are employed in a molar ratio of 1 : 3 to 1 : 8.
3. Process according to claim 1, characterized in that the triethylamine is employed in a molar ratio to the 2-amino-4,6- dihydroxypyrimidine of 2 : 1 to 3 : 1.
4. Process according to claim 1, characterized in that, to isolate the 2-amino-4,6-dichloropyrimidine, excess phosphorus oxychloride is distilled off in vacuo, the residue is suspended in water at 40 - 60°C, after stirring for 1.5 to 2.5 hours, 20 - 50% strength NaOH is added to the suspension thus obtained until a pH of about 2.5 to 4 is reached, after which the 2-amino-4,6-dichloropyrimidine which has precipitated out is filtered off, washed with water and dried in air.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0099594A AT402924B (en) | 1994-05-13 | 1994-05-13 | METHOD FOR PRODUCING 2-AMINO-4,6-DICHLORO-PYRIMIDINE |
| ATA995/94 | 1994-05-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2149273A1 true CA2149273A1 (en) | 1995-11-14 |
Family
ID=3504526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002149273A Abandoned CA2149273A1 (en) | 1994-05-13 | 1995-05-12 | Process for the preparation of 2-amino-4,6-dichloro-pyrimidine |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5563270A (en) |
| EP (1) | EP0682018B1 (en) |
| JP (1) | JPH0841034A (en) |
| KR (1) | KR950032139A (en) |
| CN (1) | CN1052226C (en) |
| AT (2) | AT402924B (en) |
| AU (1) | AU682261B2 (en) |
| CA (1) | CA2149273A1 (en) |
| CZ (1) | CZ287703B6 (en) |
| DE (1) | DE59502219D1 (en) |
| DK (1) | DK0682018T3 (en) |
| ES (1) | ES2116007T3 (en) |
| FI (1) | FI952287A (en) |
| HR (1) | HRP950262B1 (en) |
| HU (1) | HU217649B (en) |
| IL (1) | IL113712A (en) |
| NO (1) | NO304309B1 (en) |
| NZ (1) | NZ272110A (en) |
| PL (1) | PL180989B1 (en) |
| SK (1) | SK282077B6 (en) |
| TW (1) | TW422839B (en) |
| YU (1) | YU26995A (en) |
| ZA (1) | ZA953886B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT402818B (en) * | 1995-06-02 | 1997-09-25 | Chemie Linz Gmbh | METHOD FOR PRODUCING PURE 4,6-DICHLORPYRIMIDINE |
| AU1935299A (en) * | 1997-12-19 | 1999-07-12 | Dow Agrosciences Llc | Chloropyrimidine process |
| EP1188750B1 (en) * | 1998-12-21 | 2003-10-15 | Lonza AG | Process for the preparation of 2,5-diamino-4,6-dihalogenopyrimidinen |
| CN101363542B (en) * | 2008-09-09 | 2012-07-25 | 王春阳 | Electric control on-off gearshift |
| CN102702110A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 4-amino-5, 6-dichloropyrimidine |
| CN109796413A (en) * | 2019-01-24 | 2019-05-24 | 安徽广信农化股份有限公司 | A kind of triethylamine recovery process for the synthesis of 4,6- dichloro pyrimidine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1055560B (en) * | 1974-05-02 | 1982-01-11 | Istituto Chemioterapico | PYRIMIDINE DERIVATIVES AND RELATED COMPOSITIONS FOR THE TREATMENT OF VIRAL INFECTIONS |
| CN1019575B (en) * | 1988-02-19 | 1992-12-23 | 石原产业株式会社 | Process for producing 2-amino-4, 6-dichloropyrimidine |
| WO1995007265A1 (en) * | 1993-09-10 | 1995-03-16 | E.I. Du Pont De Nemours And Company | Improved process for preparing 2-amino-4,6-dichloropyrimidine |
-
1994
- 1994-05-13 AT AT0099594A patent/AT402924B/en not_active IP Right Cessation
-
1995
- 1995-04-26 DK DK95106196T patent/DK0682018T3/en active
- 1995-04-26 DE DE59502219T patent/DE59502219D1/en not_active Expired - Fee Related
- 1995-04-26 EP EP95106196A patent/EP0682018B1/en not_active Expired - Lifetime
- 1995-04-26 ES ES95106196T patent/ES2116007T3/en not_active Expired - Lifetime
- 1995-04-26 AT AT95106196T patent/ATE166349T1/en not_active IP Right Cessation
- 1995-04-28 YU YU26995A patent/YU26995A/en unknown
- 1995-04-28 HR HRA995/94A patent/HRP950262B1/en not_active IP Right Cessation
- 1995-05-10 TW TW084104635A patent/TW422839B/en not_active IP Right Cessation
- 1995-05-11 CN CN95105375A patent/CN1052226C/en not_active Expired - Fee Related
- 1995-05-11 JP JP7113351A patent/JPH0841034A/en not_active Ceased
- 1995-05-11 FI FI952287A patent/FI952287A/en unknown
- 1995-05-12 AU AU20033/95A patent/AU682261B2/en not_active Ceased
- 1995-05-12 CA CA002149273A patent/CA2149273A1/en not_active Abandoned
- 1995-05-12 KR KR1019950011647A patent/KR950032139A/en active IP Right Grant
- 1995-05-12 HU HU9501404A patent/HU217649B/en not_active IP Right Cessation
- 1995-05-12 SK SK621-95A patent/SK282077B6/en unknown
- 1995-05-12 IL IL11371295A patent/IL113712A/en not_active IP Right Cessation
- 1995-05-12 PL PL95308578A patent/PL180989B1/en unknown
- 1995-05-12 ZA ZA953886A patent/ZA953886B/en unknown
- 1995-05-12 NZ NZ272110A patent/NZ272110A/en unknown
- 1995-05-12 CZ CZ19951234A patent/CZ287703B6/en not_active IP Right Cessation
- 1995-05-12 US US08/440,257 patent/US5563270A/en not_active Expired - Fee Related
- 1995-05-12 NO NO951889A patent/NO304309B1/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |